This proposal is in response to NIDCR PAR-09-182 Small Grants for Data Analysis, to support research that involves secondary data analyses using existing oral health conditions from databases which can be conducted in a short time period. We will use data collected through the International Head and Neck Cancer Epidemiology (INHANCE) Consortium established by NCI/IARC in response to limitations in research of rare tumors, including head and neck cancer (HNC) and its subsites. INHANCE is based on collaboration of large molecular/genetic epidemiology studies of HNC worldwide. We propose to examine human papillomavirus (HPV), a recently identified risk factor for a significant proportion of HNC cases. There are several issues that remain unclear about its relation to HNC and to tobacco and alcohol which the INHANCE pooled analysis will better clarify. The aims in this study are to: Aim 1. examine the association between HPV, tobacco, alcohol and risk of HNC to determine whether there are two HNC diseases, one risk group related to HPV and the other related to tobacco/alcohol. To evaluate this issue, we propose a) a case/control study stratifying the association of three risk factors using previously collected demographic and risk factor data from the INHANCE Consortium Centers and their HPV serology databases; and b) a case/case comparison of HPV, tobacco, and alcohol risk factors in tumor HPV DNA-positive (+) compared to tumor HPV DNA-negative (-) cases to determine whether there is a difference in risk factors. Rationale: Whereas some studies show that HPV-infected tumors are associated with nontobacco and/or nonalcohol use and HPV- HNC tumors are associated with tobacco/alcohol use, other studies show no differences in risk by HPV status and tobacco/alcohol use. This large sample size analysis should clarify whether there are two or more risk factor profiles of HNC. Aim 2. compare tumor tissue HPV DNA+ findings in HNC cases for E6/E7 antibodies, evaluating tumor HPV DNA+/sero- to HPV DNA+/sero+ and DNA-/sero- cases. The aim will determine whether there are HPV-driven and HPV-independent HNC and whether HPV DNA+/sero- cases have risk factors similar to or different from HPV DNA+/sero+ or HPV DNA-/sero- cases. Rationale: Some patients with HNC HPV DNA+ tumors do not mount an immunologic response, suggesting that these cases have different risk factors and clinical outcomes than do HPV antibody positive cases. PUBLIC HEALTH RELEVANCE: Determining HPV-driven tumor status prior to diagnosis using blood before tumor tissue is available, and that accurately reflects an HPV-driven HNC tumor based on antibody response, will provide information for treatment specifically targeted to HPV-driven tumors; and predict survival which is significantly better in HPV DNA-driven tumors. This larger study will clarify whether there are two or more risk factor profiles of HNC suggesting that causes other than tobacco/alcohol lead to HPV-HR cancer.